Scholarly article on topic 'Research on the modern clinical herbal administration rules in TCM treatment of ovarian cysts based on data mining'

Research on the modern clinical herbal administration rules in TCM treatment of ovarian cysts based on data mining Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Ya'nan Song, Jianpeng Hu, Haiyan Wang, Lina Wang, Xiaojuan Li, et al.

Abstract Objective To explore the recent 20 years' herbal administration rules in TCM treatments of ovarian cysts (OCs) based on data mining. Methods A prescription database for ovarian cysts was established by ACCESS 2007. Importing the database into SPSS17.0 and SPSS Modeler14.1. SPSS17.0 was used for descriptive and cluster analyses, while SPSS Modeler14.1 was used for association rules analysis. Results After screening, 363 prescriptions were obtained. The 10 most frequently-used Chinese herbal medicines are Zedoaria (Rhizoma Curcumae), Poria cocos (Poria), Common buried rubber (Rhizoma Sparganii), Red peony root (Radix Paeoniae Rubra), Peach seed (Semen Persicae), Danggui (Radix Angelicae Sinensis), Chinese angelica (Ramulus Cinnamomi), Liquorice root (Radix Glycyrrhizae), Pangolin scales (Squama Manis) and Moutan cortex (Cortex Moutan Radicis); the 5 most common syndromes of OCs are qi stagnation and blood stasis, phlegm and blood stasis, uterine blood stasis, stagnation of liver qi and retention of phlegm and dampness, nearly to 54.26%; In association rules analysis, 5 sets of two-herbs association rules were obtained, 17 sets of three-herbs association rules were obtained, 22 sets of four-herbs association rules were obtained and 4 sets of five-herbs association rules were obtained; By clustering, 13 sets of core couplet medicinals were obtained. Conclusion Medicinal herbs for promoting blood circulation to remove blood stasis, resolve hard lumps, for strengthening the spleen, eliminating phlegm, and relieving liver qi stagnation were highly used in the treatment of OCs; Herbs attributed to the Liver Meridian, the Spleen Meridian and the Heart Meridian were highly used in OCs; The compatibility of herbs for promoting blood circulation to remove blood stasis and resolve hard lumps were highly used; Guizhi Fuling Wan (GFW) was often used and combined with other herbs in the treatment of OCs.

Academic research paper on topic "Research on the modern clinical herbal administration rules in TCM treatment of ovarian cysts based on data mining"

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Traditional Chinese Medical Sciences

Research on the modern clinical herbal administration rules in TCM treatment of ovarian cysts based on data mining

Ya'nan Song, Jianpeng Hu, Haiyan Wang, Lina Wang, Xiaojuan Li, Yun Pan, Feifei Bu, Jian Wang

PII: S2095-7548(17)30081-9

DOI: 10.1016/j.jtcms.2017.07.005

Reference: JTCMS 114

To appear in: Journal of Traditional Chinese Medical Sciences

Received Date: 13 May 2017 Revised Date: 11 July 2017 Accepted Date: 13 July 2017

Please cite this article as: Song Y'n, Hu J, Wang H, Wang L, Li X, Pan Y, Bu F, Wang J, Research on the modern clinical herbal administration rules in TCM treatment of ovarian cysts based on data mining, Journal of Traditional Chinese Medical Sciences (2017), doi: 10.1016/j.jtcms.2017.07.005.

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Research on the modern clinical herbal administration rules in TCM

treatment of ovarian cysts based on data mining

Ya'nan Songa, Jianpeng Hub, Haiyan Wanga, Lina Wangb,Xiaojuan Lia,Yun Pana,

b b * Feifei Bu , JianWang '

aBeijing University of Chinese Medicine, Beijing 100029, China hAnhui University of Chinese Medicine, Hefei230038, China Corresponding author.

E-mail address:wangjian6301@163.com (J. Wang). Abstract

Objective:To explore the recent 20 years' herbal administration rules in TCM treatments of ovarian cysts (OCs) based on data mining.

Methods: A prescription database for ovarian cysts was established by ACCESS2007.Importing the database into SPSS17.0(SPSS Inc., Chicago, IL, USA)and SPSS Modeler14.1(SPSS Inc., Chicago, IL, USA).SPSS17.0 (SPSS Inc., Chicago, IL, USA)was used for descriptive and cluster analyses, while SPSS Modeler14.1 (SPSS Inc., Chicago, IL, USA) was used for association rules analysis. Results: After screening, 363 prescriptions were obtained. The10 most frequently-used Chinese herbal medicines are Ezhu(Rhizoma Curcumae), Fuling(Poria), Sanleng (Rhizoma Sparganii), Chishao(Radix Paeoniae Rubra), Taoren(Semen Persicae), Danggui(Radix Angelicae Sinensis), Guizhi(Ramulus Cinnamomi), Gancao(Radix Glycyrrhizae), Chuanshanjia(Squama Manis)and Mudanpi(Cortex Moutan Radicis); the 5 most common syndromes of OCs are qi stagnation and blood stasis, phlegm and blood stasis , uterine blood stasis, stagnation of liver qi and retention of phlegm and dampness, nearly to 54.26%; In association rulesanalysis, 5sets of two-herbs association rules were obtained, 17sets of three-herbs association rules were obtained, 22 sets of four-herbs association rules were obtained and 4 sets of five- herbs association rules were obtained; By clustering, 13sets of core couplet medicinals were obtained.

Conclusion: Medicinal herbs for promoting blood circulation to remove blood stasis, resolve hard lumps, for strengthening the spleen, eliminating phlegm, and relieving liver qi stagnation were highly used in the treatment of OCs; Herbs attributed to the Liver Meridian, the Spleen Meridian and the Heart Meridian were highly used in OCs; The compatibility of herbs for promoting blood circulation to remove blood stasis and resolve hard lumps were highly used; Guizhi Fuling Wan (GFW)was often used and combined with other herbs in the treatment of OCs.

KEYWORDS

Ovarian cysts; Data mining; Traditional Chinese medicine; Herbal administration rules

Introduction

Ovarian cysts (OCs) are common gynecological tumors among women aged of 20 to 50.1 There are no obvious symptoms in the early stage. When the cysts get enlarged, the cysts may cause abdominal discomfort, abnormal leucorrhea, menstrual disorders, palpable abdominal masses, and even palpitation, frequent urination and chest oppressive symptoms. If effective treatment does not follow, severe lesions may occur, including OCs pedicle torsion, rupture, or secondary infection.

In recent years, the incidence of OCs has increased because of the aggravation of environmental pollution and increasedstress.4 Currently, Western medicine often employs laparoscopic surgery and transvaginal surgery for OCs. However, many clinical studies have revealed that after removal of OCs, the number of primary follicles was significantly reduced compared with that of the contralateral ovary, which can affect ovulation and fertility.5 In contrast, TCM treatment for OCs is a non-invasive approach that aims to relieve the pain after surgery with no obvious side effects.

Data mining (DM) is the process of extracting previously unknown and latent useful information and knowledge from a vast amount of incomplete, noisy, vague and random data.6DM technology has been applied to TCM research since the 1990s, and to date, DM has been applied to almost all areas of TCM research, including TCM diagnosis, syndrome differentiation, pharmacy, pharmacology, and physician

experience. DM has greatly promoted the development of TCM. ,

To explore the herbal administration rules in the treatment of OCs, this study analyzed 363 TCM prescriptions listed in the modern literature from 1996 to 2016 by DM. The goal of this work was to provide valuable treatment ideas and herbal administration rules in the treatment of OCs with TCM.

Data and Methods Data sources

Using "ovarian cysts" and "traditional Chinese medicine" as the key words, we searched the modern literature on OCs published between January 1, 1996 and December 31, 2016, including clinical experience, case reports and clinical observations from CNKI; a total of 698 articles were obtained. After screening, a total of 363 prescriptions were obtained. The following data was entered into an Access 2007 database: number, syndrome, name of prescriptions, herbs and meridian tropism of herbs.

Inclusion criteria and exclusion criteria

The inclusion criteria were as follows:

(a)Patients were clearly diagnosed as ovarian cysts by Western medicine according to

B-ultrasound examination, X-ray examination, CT examination or MRI examination, combined with clinical manifestations, cytological examination and laparoscopy. 9

(b)TCM treatment was applied, and the ovarian cysts were reduced by at least 30% according to imaging examination after TCM treatment.

(c) TCM prescription composition was clearly described.

(d) The dosage form was herbal decoction.

The exclusion criteria were as follows:

(a) Literature with no definite diagnosis of ovarian cysts by Western medicine.

(b)TCM treatment was supplied as an adjuvant therapy.

(c)The group treated by integrated traditional Chinese and Western medicine with success.

(d)Studies repeatedly cited were considered only once. Methods

Data standardization and database establishment

(a) Data standardization: Referring to the 11th Five-Year Planning Textbook "Chinese medicine10", the names of the Chinese herbal medicinals were standardized. Referring to the "TCM clinical terminology11", the syndromes were standardized.

(b)Database establishment: An OCs prescription database was created using Access 2007and imported into SPSS17.0 (SPSS Inc., Chicago, IL, USA)and SPSS Modeler14.1 (SPSS Inc., Chicago, IL, USA).

Research methods

(a)Frequency analysis: Frequency of the herbs prescribed, frequency of herbs meridian tropism and frequency of syndrome were performed by SPSS17.0 (SPSS Inc., Chicago, IL, USA).

(b)Association rules analysis: Two-herbs association rules, three-herbs association rules, four-herbs association rules and five-herbs association rules were performed using Apriori algorithm in the SPSS Modeler 14.1 (SPSS Inc., Chicago, IL, USA).

(c) Cluster analysis: Cluster analysis was performed on the herbs that have been used more than 30 times usingSPSS17.0 (SPSS Inc., Chicago, IL, USA).

Results:

Frequency analysis of the herbs prescribed

In the analysis of the frequency of 363prescriptions, 225 herbal medicinals were obtained; the total herb use frequency was 4330. In terms of the order of frequency, the herbs with ratio greater than or equal to 10% are listed in Table 1.

Table 1 Frequency distribution of the herbs prescribed.

Herbs Frequency Ratio

EzhuRhizoma Curcumae) 190 52.34%

Fuling (Poria) 184 50.69%

Sanleng(Rhizoma Sparganii) 175 48.21%

Chishao (Radix Paeoniae Rubra) 173 47.66%

Taoren(Semen Persicae) 158 43.53%

Danggui(Radix Angelicae Sinensis) 152 41.87%

Guizhi(Ramulus Cinnamomi) 144 39.67%

Gancao (Radix Glycyrrhizae) 113 31.13%

Chuanshanjia(Squama Manis) 110 30.30%

Mudanpi (Cortex Moutan Radicis) 101 27.82%

Danshen(Radix Salviae Miltiorrhizae) 98 27.00%

Xiangfu(Rhizoma Cyperi) 95 26.17%

Baishao(Radix Paeoniae Alba) 91 25.07%

Chuanxiong(Rhizoma Ligustici Chuanxiong) 88 24.24%

Huangqi(Radix Astragali seu Hedysari) 79 21.76%

Muli(Concha Ostreae) 78 21.49%

Xiakucao(Spica Prunellae) 73 20.11%

Baizhu(Rhizoma Atractylodis Macrocephalae) 72 19.83%

Zhebeimu(Bulbus Fritillariae Thunbergii) 71 19.56%

Yiyiren(Semen Coicis) 67 18.46%

Chaihu(Radix Bupleuri) 67 18.46%

Haizao(Sargassum) 67 18.46%

Shuizhi(Hirudo) ^63 17.36%

Zaojiaoci (Spina Gleditsiae) 57 15.70%

Biejia(Carapax Trionycis) 54 14.88%

Niuxi(Radix Achyranthis Bidentatae) 51 14.05%

Yanhusuo(Rhizoma Corydalis) 47 12.95%

Honghua(Flos Carthami) 47 12.95%

Dangshen(Radix Codonopsis) 47 12.95%

Zhike(Fructus Aurantii) 44 12.12%

Kunbu(Thallus Laminariae) 41 11.29%

Yimucao(Herba Leonuri) 40 11.02%

Banxia(Rhizoma Pinelliae) 39 10.74%

Baijiangcao(Herba Patriniae) 37 10.19%

The frequency analysis of herbs revealed that the top ten frequentlyused herbs areEzhu (Rhizoma Curcumae), Fuling(Poria), Sanleng(Rhizoma Sparganii), Chishao(Radix Paeoniae Rubra), Taoren(Semen Persicae), DangguiRadix Angelicae Sinensis),Guizhi(Ramulus Cinnamomi), GancaoRadix Glycyrrhizae), Chuanshanjia(Squama Manis), and Mudanpi(Cortex Moutan Radicis).According to the classification of traditional Chinese medicine, Ezhu(Rhizoma Curcumae), Chishao(Radix Paeoniae Rubra), Sanleng(Rhizoma Sparganii), Taoren(Semen Persicae), and Chuanshanjia(Squama Manis) belong to herbs that activate blood circulation.10 Although GuizhiRamulus Cinnamomi) belongs to herbs for relieving the exterior syndrome, itcan also warm meridians.10Danggui(RadixAngelicae Sinensis)can enrich bloodand promote blood circulation to restore menstrual

flow.10Mudanpi(Cortex Moutan Radicis) and Chishao(Radix Paeoniae Rubra) can eliminate pathogenic heat from the blood and activate blood circulation to dissipate blood stasis.10Fuling(Poria) can clear dampness and induce urination, strengthen the spleen and resolve phlegm.10

Frequency of herbs meridian tropism

Frequency analysis was conducted on the meridian tropism of 225 herbs collected. The frequency of meridian tropism is listed in Table 2.

Table 2Meridian tropism and frequency of herbs.

Meridian tropism of herbs Frequency Ratio

Liver Meridian 3268 22.61%

Spleen Meridian 2965 20.51%

Heart Meridian 1680 11.62%

Kidney Meridian 1527 10.56%

Stomach Meridian 1348 9.32%

Lung Meridian 1069 7.39%

Large Intestine Meridian 825 5.71%

Gallbladder Meridian 586 4.05%

Bladder Meridian 421 2.91%

Pericardium Meridian 325 2.25%

Small Iintestine Meridian 229 1.58%

Triple Energizer Meridian 213 1.47%

In terms of the order of frequency, the meridian tropism of herbs is the Liver Meridian, Spleen Meridian, Heart Meridian, Kidney Meridian, Stomach Meridian, Lung Meridian, Large Intestine Meridian, Gallbladder Meridian, Bladder Meridian, Pericardium Meridian, Small Intestine Meridian and Triple Energizer Meridian. Obviously, the Liver Meridian, Spleen Meridian, Heart Meridian, Kidney Meridian and Stomach Meridian account for a large proportion, accumulated to 74.62%, which revealed that the herbs acted on the Liver Meridian, Spleen Meridian, Heart Meridian, Kidney Meridian and Stomach Meridian were widely used in the treatment of OCs.

Frequency analysis of syndrome

Because the pathogenesis of OCs is complicated, compound syndromes occupy a large proportion. By standardizing and classifying the syndromes, 21 standard syndromes were obtained. In terms of the order of frequency, the syndromes with frequency greater than or equal to 5 are listed in Table 3.

Table 3Frequency distribution of syndrome.

Syndrome Frequency Ratio

Qi stagnation and blood stasis 57 15.70%

Phlegm and blood stasis 48 13.22%

Uterine blood stasis 35 9.64%

Stagnation of liver qi 31 8.54%

Rention of phlegm and dampness 26 7.16%

Liver qi stagnation and spleen deficiency 23 6.34%

Accumulated damp-heat 19 5.23%

Cold coagulation and blood stasis 19 5.23%

Liver qi depression and kidney deficiency 17 4.68%

Yang deficiency of the Spleen and Kidney 14 3.86%

Deficiency of liver and kidney qi 9 2.48%

Damp-, heat and toxin 6 1.65%

Deficiency of qi and blood 5 1.38%

Disharmony between the Chong and Ren Meridians 5 1.38%

Frequency analysis of syndrome results showed that the most 5 common syndromes of OCs were qi stagnation and blood stasis, phlegm and blood stasis, uterine blood stasis, stagnation of liver qi and retention of phlegm and dampness, accumulated to 54.26%.Among them, the frequency of qi stagnation and blood stasis was 57 and the ratio was 15.7%, accounting for the highest proportion.

Association rule analysis results

Association rules reflected the knowledge of the dependence or association between

events in a data set. The important feature of association rules is an "association

natural combination", which indicates that a subset of all the attributes is very 12

useful. The default minimum support of an a priori algorithm was 10%, and the minimum confidence was 80%. By repeatedly adjusting the support and confidence, 5 sets of two-herbs association rules were obtained; 17 sets of three-herbs association rules were obtained; 22 sets of four-herbs association rules were obtained; 4 sets of five-herb association rules were obtained. The analytical results of the association between different herbs are presented in Table 4, Table 5, Table 6 and Table 7.

Table 4Two-herbs association rules.

Consequent Antecedent Support (%) Confidence (%)

Ezhu = T Sanleng = T 48.209 91.429

Fuling = T Mudanpi = T 27.824 86.139

Guizhi = T Mudanpi = T 27.824 84.158

Fuling = T Baizhu = T 19.835 83.333

Taoren = T Mudanpi = T 27.824 81.188

Table 5Three-herbs association rules.

Consequent Antecedent Support (%) Confidence (%)

Ezhu = T Biejia = T and Sanleng = T 10.468 97.368

Ezhu = T Xiangfu = T and Sanleng = T 13.223 93.75

Ezhu = T Fuling = T and Sanleng = T 20.386 93.243

Fuling = T Mudanpi = T and Taoren = T 22.59 92.683

Ezhu = T Chishao = T and Sanleng = T 22.314 92.593

Ezhu = T Shuizhi = T and Sanleng = T 10.468 92.105

Ezhu = T Muli = T and Sanleng = T 10.468 92.105

Ezhu = T Haizao = T and Sanleng = T 10.193 91.892

Fuling = T Mudanpi = T and Guizhi = T 23.416 91.765

Ezhu = T Huangqi = T and Sanleng = T 12.948 91.489

Ezhu = T Chuanxiong = T and Sanleng = T 12.948 91.489

Ezhu = T Taoren = T and Sanleng = T 21.763 91.139

Ezhu = T Danggui = T and Sanleng = T 20.386 90.541

Guizhi = T Mudanpi = T and Chishao = T 17.355 90.476

Ezhu = T Guizhi = T and Sanleng = T 17.080 90.323

Guizhi = T Mudanpi = T and Taoren = T 22.590 90.244

Ezhu = T Xiakucao = T and Sanleng = T 13.774 90.000

Table 6Four-herbs association rules.

Consequent Antecedent Support (%) Confidence (%)

Ezhu = T Biejia = T and Chishao = T and Sanleng = T 5.234 100.000

Sanleng = T Zaojiaoci = T and Chuanshanjia = T and Ezhu = T 5.785 100.000

Ezhu = T Xiakucao = T and Chishao = T and Sanleng = T 5.510 100.000

Ezhu = T Xiangfu = T and Chishao = T and Sanleng = T 5.510 100.000

Ezhu = T Chuanshanjia = T and Chishao = T and Sanleng = T 7.438 100.000

Fuling = T Baishao = T and Mudanpi = T and Taoren = T 8.540 96.774

Guizhi = T Mudanpi = T and Fuling = T and Chishao = T 15.152 96.364

Ezhu = T Huangqi = T and Chishao = T and Sanleng = T 7.438 96.296

Ezhu = T Zaojiaoci = T and Chuanshanjia = T and Sanleng = T 6.061 95.455

Sanleng = T Xiakucao = T and Danggui = T and Ezhu = T 6.061 95.455

Ezhu = T Muli = T and Chuanshanjia = T and Sanleng = T 5.785 95.238

Taoren = T Mudanpi = T and Chuanshanjia = T and Fuling = T 5.785 95.238

Ezhu = T Xiangfu = T and Taoren = T and Sanleng = T 5.785 95.238

Ezhu = T Biejia = T and Taoren = T and Sanleng = T 5.510 95.000

Ezhu = T Muli = T and Chishao = T and Sanleng = T 5.510 95.000

Ezhu = T Shuizhi = T and Chishao = T and Sanleng = T 5.234 94.737

Fuling = T Baizhu = T and Chaihu = T and Baishao = T 5.234 94.737

Ezhu = T Chuanshanjia = T and Taoren = T and Sanleng = T 9.091 93.939

Guizhi = T Baishao = T and Mudanpi = T and Taoren = T 8.540 93.548

Ezhu = T Chuanxiong = T and Chishao = T and Sanleng = T 7.163 92.308

Ezhu = T Huangqi = T and Fuling = T and Sanleng = T 6.612 91.667

Ezhu = T Xiakucao = T and Danggui = T and Sanleng = T 6.336 91.304

Table 7Five-herbsassociation rules.

Consequent Antecedent Support (%) Confidence (%)

Fuling = T Mudanpi = T and Taoren = T and Chishao = T and Ezhu = T 6.336 91.304

Fuling = T Mudanpi = T and Chishao = T and Sanleng = T and Ezhu = T 6.336 91.304

Sanleng = T Guizhi = T and Taoren = T and Fuling = T and Ezhu = T 8.815 90.625

Taoren = T Mudanpi = T and Guizhi = T and Fuling = T and Chishao = T 14.601 90.566

In this study, all sets of association rules were ranked by confidence. Confidence refers to the probability that the consequent appears when the antecedent occurs, while support refers to the probability of the antecedent and consequent appearing at the same time. For instance, the support of Sanleng(Rhizoma Sparganii)=> Ezhu(Rhizoma Curcumae)was 48.209%and the confidence was 91.429%, which showed that the probability ofSanleng(Rhizoma Sparganii) and Ezhu(Rhizoma Curcumae) being used at the same time was 48.209%, and when Sanleng(Rhizoma Sparganii)wasused, the probability ofEzhu(Rhizoma Curcumae) also being used is 91.429%.

According to the results, combined herbs were often used for invigorating blood circulation and eliminating stasis, regulating qi and activating blood, especially for resolving phlegm and activating blood. For instance, Sanleng (Rhizoma Sparganii)=>Ezhu(RhizomaCurcumae), Biejia(CarapaxTrionycis)

+Sanleng(RhizomaSparganii)=>Ezhu(Rhizoma Curcumae) ,Xiangfu(Rhizoma

Cyperi)+Sanleng (RhizomaSparganii)=> Ezhu(Rhizoma

Curcumae),Biejia(CarapaxTrionycis) + Chishao(Radix Paeoniae Rubra)+ Sanleng(Rhizoma Sparganii)=> Ezhu(RhizomaCurcumae) ,Zaoj iaoci(Spina Gleditsiae)+Chuanshanjia(Squama Manis)+Ezhu(Rhizoma

Curcumae)=>Sanleng(Rhizoma Sparganii), Mudanpi (Cortex Moutan Radicis)+Taoren(Semen Persicae)+Chishao(Radix Paeoniae Rubra)+ Ezhu(RhizomaCurcumae)=> Fuling (Poria),etc.

Cluster analysis results

The purpose of clustering is reasonable according to certain rules of classification or clustering and with the explicit or implicit method to describe the different

categories. Theseherbs that have been used more than 30 times were analyzed in terms of cluster analysis. In this analysis herb used less than 30times were not included. Basic information about the core herbs obtained from the results of cluster analysis is presented in Fig.1.

Dendrogram using Average Linkage (Between Groups)

Reseated Distance Cluster Combine

10 15 20

Baijiangcao 34

Hongteng 33

Jineijin 37

Tubiechong 38

Zexie 40

Banxia 33

Chenpi 36

Baijiezi 35

Dangshen 29

Zhiqiao 30

Yimucao 32

Yanhusuo 27

Honghua 28

Niuxi 26

Zaojiaoci 24

Haizao 22

Kunbu 31

Biejia 25

Shuizhi 23

Yiyiren 20

Xiakucao 17

Muli 16

Zliebeiniu 19

Huangqi 15

Baizhu 18

Chaihu 21

Baishao 13

Danshen 11

Xiangfu 12

Chuanshanjia 9

Gancao 8

Danggui 0

Chuanxiong 14

Guiziii 7

Danpi 10

Taoren 5

Fuling 3

Chishao 4

Ezhu 1

Sanleng 2

Figure 1Clustering tree.

By clustering, 13sets of core couplet medicines were obtained:

1. Sanleng(Rhizoma Sparganii)&Ezhu(RhizomaCurcumae),

2. Guizhi(RamulusCinnamomi) & Mudanpi (Cortex Moutan Radicis)&Taoren(Semen Persicae)&Fuling(Poria) &Chishao (Radix Paeoniae Rubra),

3. Guizhi (Ramulus Cinnamomi)& Mudanpi (Cortex Moutan Radicis),

4. DangguiRadix Angelicae Sinensis)&Chuanxiong(RhizomaLigusticiChuanxiong),

5. BaizhuRhizoma Atractylodis Macrocephalae)& ChaihuRadix Bupleuri) &Baishao(Radix Paeoniae Alba),

6. ChaihuRadix Bupleuri)& BaizhuRhizoma Atractylodis Macrocephalae),

7. Muli(Concha Ostreae) &Zhebeimu(Bulbus Fritillariae Thunbergii),

8. Haizao(Sargassum) & Kunbu(Thallus Laminariae),

9. DanshenRadix Salviae Miltiorrhizae)&Zhike(Fructus Aurantii),

10. Banxia(Rhizoma Pinelliae)& Chenpi(Pericarpium Citri Reticulata)&Baijiezi (Semen sinapis),

11. Banxia(Rhizoma Pinelliae)+ Chenpi (Pericarpium Citri Reticulata),

12. Jineijin(Endothelium Corneum Gigeriae Galli)&Tubiechong(Eupolyphaga Seu Steleophaga),

13. Hongteng(Sargentodoxa cuneata)&Baijiangcao(Herba Patriniae). Discussion

Although there is no such a term of OCs in traditional Chinese Medicine, it is in the range of Zhengjia, Jiju, and Changtan.14 From the perspective of TCM, there are many pathogenic mechanisms of OCs, and the most common are qi stagnation and blood stasis, phlegm retention, deficiency of the spleen and kidney, Uterine blood stasis and stagnation of liver qi.15 TCM attaches importance to the unified treatment, the organ function, and disharmony between qi and blood causes pathological changes of the local tissue Therefore, treatment according to syndrome differentiation is adopted, and different therapies are applied to different patients to regulate the endocrine system and improve the body immunity without damaging the patient's vitality. We hope that by obtaining these statistics and mining the effective cases in modern literature, can we provide positive guidance for TCM treatment of OCs.

According to this review of OCs studies published from January 1, 1996 to December 31, 2016 from CNKI, including clinical experience, case reports and clinical observations, we found that the syndrome of OCs is quite complex and is a combination of deficiency and excess in the TCM perspective .Nevertheless, there is still a rule to follow. The common pathogenesis is qi stagnation and blood stasis, phlegm retention and blood stasis; the most common treating methods are promoting blood circulation to remove blood stasis. Through DM, the author objectively has grasped the status and rules of herbal administration in the existing literature on OCs, and the results indicate that the use of herbs is consistent with the pathogenesis of OCs.

Frequently-used herbs for OCs

The DM results indicate that the herbal medicinals with frequency greater than 50 are as follows: Ezhu(Rhizoma Curcumae), Fuling(Poria), Sanleng(Rhizoma Sparganii), ChishaoRadix Paeoniae Rubra), Taoren(Semen Persicae), DangguiRadix Angelicae Sinensis), Guizhi (Ramulus Cinnamomi), Gancao (Radix Glycyrrhizae),

Chuanshanjia(Squama Manis) ,Mudanpi(Cortex Moutan Radicis), Danshen(Radix Salviae Miltiorrhizae), Xiangfu(Rhizoma Cyperi), Baishao(Radix Paeoniae Alba), Chuanxiong(Rhizoma Ligustici Chuanxiong), Huangqi(Radix Astragali seu Hedysari), Muli(Concha Ostreae), Xiakucao(Spica Prunellae), Baizhu(Rhizoma Atractylodis Macrocephalae), Zhebeimu(Bulbus Fritillariae Thunbergii), Yiyiren(Semen Coicis), Chaihu(Radix Bupleuri), Haizao(Sargassum), Shuizhi(Hirudo), Zaojiaoci(Spina Gleditsiae), Biejia(Carapax Trionycis) and Niuxi(Radix Achyranthis Bidentatae). Among these high-frequency medicinals herbs for promoting blood circulation to remove blood stasis account for a large proportion. They are Ezhu(Rhizoma Curcumae) ,Sanleng(Rhizoma Sparganii), Chishao(Radix Paeoniae Rubra), Taoren(Semen Persicae), Danggui(Radix Angelicae Sinensis), Chuanshanjia(Squama Manis), Danshen(Radix Salviae Miltiorrhizae), Shuizhi(Hirudo) and Niuxi(Radix Achyranthis Bidentatae).110 In addition,Muli(Concha Ostreae), Xiakucao(Spica Prunellae), Zhebeimu(Bulbus Fritillariae Thunbergii), Haizao(Sargassum) and Biejia(Carapax Trionycis)effect to resolvehard lumps.10 Although Guizhi(Ramulus Cinnamomi)belongs to herbs that relieve the exterior syndrome, it can also warm meridians. Chishao(Radix Paeoniae Rubra) and Mudanpi (Cortex Moutan Radicis)effect to eliminate pathogenic heat from blood and activate blood circulation to dissipate blood stasis. Fuling(Poria), Baizhu(Rhizoma Atractylodis Macrocephalae) and Yiyiren(Semen Coicis)can clear dampess, induce urination, strengthen the spleen and resolve phlegm10Xiangfu (Rhizoma Cyperi) and Chaihu(Radix Bupleuri)can disperse stagnated liver qi to relieve qi stagnation.10 In summary, according to the classification of TCM, herbs for promoting blood circulation to remove blood stasis, resolve hard lumps, for strengthening the spleen, resolving phlegm, and relieving liver qi stagnation is highly used in the treatment of OCs.

In terms of the order of frequency, the meridian tropisms of herbs were arranged in the order of the Liver, Spleen, Heart, Kidney, Stomach, Lung, Large Intestine, Gallbladder, Bladder, Pericardium, Small Intestine and Triple Energizer. The Liver, Spleen and Heart Meridians rank the first three. According to Chinese medicine, the liver, spleen and heart are closely connected with blood.16 The liver stores blood, and at the same time it rules smooth qi flow. The spleen governs blood, it not only is the crucial link in the process by which food is transformed into qi and blood, and it also governs blood in the sense that it keeps blood flowing in its proper paths. The heart rules blood and blood vessels, which states that the heart regulates the flow of blood.16 The results revealed that herbs for OCs were closely related to blood regulation.

Common syndromes of OCs

By statistical analysis, 21 standard syndromes of OCs were obtained, and the 5 most commonly-seen syndromes were qi stagnation and blood stasis, phlegm and blood stasis, uterine blood stasis, stagnation of liver qi and retention of phlegm and dampness, accumulated to 54.26%. Among them, the frequency of qi stagnation and blood stasis is 57 and the ratio is 15.7%, accounting for the highest proportion. The

frequency of phlegm and blood stasis was 48, and the ratio was 13.22%. The frequency of uterine blood stasis was 35, and the ratio was 9.64%. Obviously, these three syndromes accounted for 38.56% and were closely related to blood stasis. Blood stasis means blood circulation is retarded, which is a consequence of the invasion by pathogenic factors or blockage of the vessels.16 In addition, the frequency of stagnation of liver qi was 31 and the ratio was 8.54%. The frequency of retention of phlegm and dampness was 26, and the ratio was 7.16%. To conclude, qi stagnation and blood stasis, phlegm and blood stasis, uterine blood stasis, stagnation of liver qi and retention of phlegm and dampness are the most commonly-seen syndromes of OCs, which is consistent with the general understanding of OCs.

Commonly-combined medicinal herbs for OCs

According to clustering analyses, the most commonly-used combined medicinal herbs are as follows:

1. Sanleng(Rhizoma Sparganii)&Ezhu(RhizomaCurcumae):

Both Sanleng(Rhizoma Sparganii)and Ezhu(RhizomaCurcumae) can promote circulation of qi to and remove blood stasis. Thus they are often employed together to relieve gynecological disorders marked by abdominal pain, abdominal mass and menstrual disorders.

2. Guizhi(RamulusCinnamomi) , Mudanpi(CortexMoutan Radicis),Taoren(Semen Persicae),Fuling(Poria) &Chishao (Radix Paeoniae Rubra):

These five herbs make up a fomula: Guizhi Fuling Wan (GFW). The acrid, warm properties of Guizhi(RamulusCinnamomi)unblock the blood vessels and reduce the stasis of blood by promoting circulation. Fuling(Poria) is used to resolve phlegm and induce urination. Chishao (Radix Paeoniae Rubra) promotes the circulation of blood to alleviate stasis. Mudanpi (Cortex Moutan Radicis) and Taoren(Semen Persicae)cool and invigorate e blood, break up and expel blood stasis, soften hard mass and remove abdominal fullness.

3. Guizhi (Ramulus Cinnamomi)& Mudanpi (Cortex Moutan Radicis) : Guizhi(Ramulus Cinnamomi) and Mudanpi (Cortex Moutan Radicis) is a pair of herbs warm and cold in property . They invigorate the circulation of blood and warm the meridians, cool blood and dissipate blood stasis.

4. Danggui(Radix Angelicae Sinensis)&Chuanxiong(RhizomaLigusticiChuanxiong): Danggui(Radix Angelicae Sinensis) tonifies blood, activates blood circulation, promotes the flow of qi, and regulates menstruation to relieve abdominal pain. The compatibility of Danggui(Radix Angelicae Sinensis) &Chuanxiong (RhizomaLigusticiChuanxiong) can promote blood and qi circulation.

5. Baizhu(Rhizoma Atractylodis Macrocephalae)& Chaihu(Radix Bupleuri) &Baishao(Radix Paeoniae Alba):

Baizhu(Rhizoma Atractylodis Macrocephalae) is often used to treat spleen deficiency complicated by retention of dampness. ChaihuRadix Bupleuri)is the main herb to soothe the liver. Baishao(Radix Paeoniae Alba) can nourish blood and soothe liver qi. The compatibility of them can soothe the liver and strengthen the spleen, nourish yin and blood.

6. Chaihu(Radix Bupleuri)& Baizhu(Rhizoma Atractylodis Macrocephalae): Chaihu(Radix Bupleuri) is used to soothe the liver and Baizhu(Rhizoma Atractylodis Macrocephalae) to treat spleen deficiency complicated by retention of dampness. The compatibility of them effects to soothe the liver and strengthen the spleen.

7. Muli(Concha Ostreae) &Zhebeimu(Bulbus Fritillariae Thunbergii): Muli(Concha Ostreae) can soften hard masses and Zhebeimu(Bulbus Fritillariae Thunbergii) is commonly used to clear heat and resolve phlegm. The compatibility of them effects to remove hard masses.

8. Haizao(Sargassum) & Kunbu(Thallus Laminariae):

Haizao(Sargassum) is bitter and salty in taste, and it can be used to soften hard masses by resovling phlegm. Kunbu(Thallus Laminariae) is often used to resolve phlegm and soften hard masses. They are used together to resolve phlegm and disintegrate masses.

9. Danshen(Radix Salviae Miltiorrhizae)&Zhike(Fructus Aurantii): Danshen(Radix Salviae Miltiorrhizae) is often used to promote the circulation of blood and eliminate bolod stasis. Zhike(Fructus Aurantii) effects to regulate the flow of qi and removeg obstruction .They are used together to promote blood and qi circulation.

10. Banxia(Rhizoma Pinelliae)& Chenpi(Pericarpium Citri Reticulata)& Baijiezi(Semen sinapis):

Banxia(Rhizoma Pinelliae) and Chenpi (Pericarpium Citri Reticulata) are used to regulate qi and resolve phlegm. Baijiezi effects to resolve phlegm and disintegrate masses. They are used together to strengthen qi regulation and resolve phlegm.

11. Banxia(Rhizoma Pinelliae)& Chenpi (Pericarpium Citri Reticulata) : Banxia(Rhizoma Pinelliae) effects to eliminate phlegm and dampness. Chenpi (Pericarpium Citri Reticulata) acts to regulate the flow of qi and clear dampness. They are used together to regulate qi and resolve phlegm.

12. Jineijin(Endothelium Corneum Gigeriae Galli)& Tubiechong(Eupolyphaga Seu Steleophaga):

Jineijin(Endothelium Corneum Gigeriae Galli) is often used to promote digestion and regulate the flow of spleen and stomach qi. Tubiechong (Eupolyphaga Seu Steleophaga) is used to promote the flow of blood to remove blood stasis. The combination of them effects to promote blood circulation to remove stagnancy.

13. Hongteng(Sargentodoxa cuneata)& Baijiangcao(Herba Patriniae). Hongteng(Sargentodoxa cuneata) has the effect of clearing heat and eliminating toxins, and clearing blood heat and promoting the circulation of blood. Baijiangcao(HerbaPatriniae) has the effect of clearing heat and eliminating toxins, and removing blood stasis. The two are used together to strengthen the effect of clearing heat and toxic substances and promoting blood circulation to dissipate blood stasis.

The application of Guizhi Fuling Wan (GFW) in the treatment of OCs

No matter in the high-frequency herbs, association rules, and clustering analyses, we

all found a signature of a famous ancient prescription: Guizhi Fuling Wan (GFW). GFW originally recorded in the book Synopsis of the Golden Chamber (Jinkui Yaolue),written by Zhang Zhongjing (150-219 AD) at the end of the Eastern Han Dynasty. GFW has been used extensively throughout Asia in the treatment of blood

stasis, and it has been proven to be very safe and effective, with few side effects. Baishao and Chishao are now used separately, but in the Golden Cabinet (Jinkui Yaolue), only Shaoyao was recorded; therefore, in this study, we considered both Baishao and Chishao were in the composition of GFW.

In the high-frequency herb analysis, all combined herbs in GFW appeared with high frequency. Furthermore, Fuling (Poria) was used 184 times, with a frequency of 50.69%; Chishao (Radix Paeoniae Rubra) was used 173 times, with a frequency of 47.66%; Taoren (Semen Persicae) was used 158 times, with a frequency of 43.53%; Guizhi (Ramulus Cinnamomi) was used 144times, with a frequency of 39.67%;Mudanpi (Cortex Moutan Radicis) was used 101 times, with a frequency of 27.82%; and Baishao (Radix Paeoniae Alba) was used 93 times, with a frequency of 25.07%. These results indicate that GFW is highly used for OCs.

In the association rules analysis, there are a large number of herb combinations related to GFW. Furthermore, the support of Mudanpi (Cortex Moutan Radicis)+ Guizhi (Ramulus Cinnamomi)+ Fuling (Poria)+ Chishao (Radix Paeoniae Rubra)=> Taoren (Semen Persicae)is 14.601% with a confidence of 90.566%; i.e.,the probability of this combination simultaneouslyoccurring in one prescription is 14.601%, and when Mudanpi (Cortex Moutan Radicis)+ Guizhi (Ramulus Cinnamomi)+ Fuling (Poria)+ Chishao (Radix Paeoniae Rubra)occur in one prescription, the probability of using Fuling is 90.566%. In addition to the one of the specifically mentioned association rules, still other association rules contain the herbs in GFW. Furthermore, in the cluster analysis, GFW was clustered as one unit. Consequently, GFW appeared in large numbers and was often combined in the treatment of OCs; therefore, GFW is an effective prescription for the treatment of OCs.

Conclusion

Based on data mining analysis, this study demonstrated that medicinal herbs for promoting blood circulation to remove blood stasis, resolve hard lumps, for strengthening the spleen, eliminating phlegm, and relieving liver qi stagnation were highly used in the treatment of OCs; Herbs attributed to the Liver Meridian, the Spleen Meridian and the Heart Meridian were highly used in OCs; The compatibility of herbs for promoting blood circulation to remove blood stasis and resolve hard lumps were highly used; The 5 most commonly-seen syndromes were qi stagnation and blood stasis, phlegm and blood stasis, uterine blood stasis, stagnation of liver qi and retention of phlegm and dampness; Guizhi Fuling Wan (GFW)was often used and combined with other herbs in the treatment of OCs.

The review of the current literature on TCM treatment for OCs reveals that a large number of doctors take advantage of syndrome differentiation and treatment with good clinical efficacy; however, weak points still exist. Most prescriptions are based personal experience and lack of widely available treatment options. There are little evidence-based medical studies for OCs. There is also a lack of DM research regarding OCs. Therefore, we believe that future studies should focus on DM and data standardization to obtain better clinical curative effects. Our results identify the most commonly-used Chinese medicinal herbs, combined herbs and association rules in the treatment of OCs. Furthermore, we have proposed the compatibility laws of herbs in the treatment of OCs. We expect that the results of this study will be used as a reference for administration of medicinal herbs in the treatment of OCs.

Funding

This study is supported by National Science and Technology Support Program (No.2013CB532001).

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